CN101160131A - Pharmaceutical combination of bcr-abl and raf inhibitors - Google Patents
Pharmaceutical combination of bcr-abl and raf inhibitors Download PDFInfo
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- CN101160131A CN101160131A CNA2006800126516A CN200680012651A CN101160131A CN 101160131 A CN101160131 A CN 101160131A CN A2006800126516 A CNA2006800126516 A CN A2006800126516A CN 200680012651 A CN200680012651 A CN 200680012651A CN 101160131 A CN101160131 A CN 101160131A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a pharmaceutical combination comprising: a) a pyrimidylaminobenzamide compound, and b) a RAF kinase inhibitor and a method for treating or preventing a proliferative disease using such a combination, wherein compound a) has the following general Formula: (I).
Description
The present invention relates to contain the pharmaceutical combination product of pyrimidylaminobenzamderivatives chemical compound and RAF inhibitor, and this class combination product is in the proliferative disease purposes in tumor, myeloma, leukemia, psoriasis, restenosis, scleroderma (sclerodermitis) and the fibrosis for example.
Although the selection of many Therapeutic Method is arranged, but still need effective and safe antiproliferative and the preferable use in combination treatment thereof for the proliferative disease patient.
Summary of the invention
Have now found that the combination product that comprises at least a pyrimidylaminobenzamderivatives chemical compound and RAF inhibitors of kinases, for example as hereinafter defined, for example tumor, myeloma, leukemia, psoriasis, restenosis, scleroderma and fibrosis have beneficial effect to proliferative disease.
Detailed Description Of The Invention
The purposes and being used to that the present invention relates to the pyrimidylaminobenzamderivatives chemical compound of formula I prepares the N-oxide or the officinal salt of this compounds of the pharmaceutical composition of treatment kinases dependence disease:
Wherein
R
1Expression hydrogen, low alkyl group, lower alkoxy-low alkyl group, acyloxy-low alkyl group, carboxyl-low alkyl group, elementary alkoxy carbonyl-low alkyl group or phenyl-low alkyl group;
R
2The expression hydrogen, randomly by one or more identical or different radicals R
3Low alkyl group, cycloalkyl, benzo cycloalkyl, heterocyclic radical, the aryl that replaces or contain zero, one, two or three theheterocyclic nitrogen atoms and the monocycle or the bicyclic heteroaryl of zero or oxygen atom and a zero or a sulphur atom, group is not replace or single replace or polysubstituted under every kind of situation;
And R
3Expression hydroxyl, lower alkoxy, acyloxy, carboxyl, elementary alkoxy carbonyl, carbamoyl, the single replacement of N-or N, N-disubstituted amido formoxyl, amino, single replacement or disubstituted amido, cycloalkyl, heterocyclic radical, aryl or contain zero, one, two or three theheterocyclic nitrogen atoms and the monocycle or the bicyclic heteroaryl of zero or oxygen atom and a zero or a sulphur atom, group are not replace or single replace or polysubstituted in each case;
Or R wherein
1And R
2Together expression is randomly replaced or dibasic alkylidene that 4,5 or 6 carbon atoms are arranged by low alkyl group, cycloalkyl, heterocyclic radical, phenyl, hydroxyl, lower alkoxy, amino, single replacement or disubstituted amido, oxo, pyridine radicals, pyrazinyl or pyrimidinyl mono; The benzo alkylidene that 4 or 5 carbon atoms are arranged; The oxa-alkylidene that 1 oxygen atom and 3 or 4 carbon atoms are arranged; Or have 1 nitrogen-atoms and 3 or 4 carbon atoms, wherein nitrogen be unsubstituted or by low alkyl group, phenyl-low alkyl group, elementary alkoxy carbonyl-low alkyl group, carboxyl-low alkyl group, carbamoyl-low alkyl group, N-is single replaces or N the azepine alkylidene that N-disubstituted amido formoxyl-low alkyl group, cycloalkyl, elementary alkoxy carbonyl, carboxyl, phenyl, substituted-phenyl, pyridine radicals, pyrimidine radicals or pyrazinyl replace;
R
4Expression hydrogen, low alkyl group or halogen.
In context of the present disclosure, except as otherwise noted, above and hereinafter used generic term preferably have following meanings:
Prefix " rudimentary " expression has at the most and comprises 7, special at the most and comprise the group of 4 carbon atoms, described group be straight chain at a place or many places the side chain of side chain is arranged.
The chemical compound of the plural number of any indication, salt etc. also are interpreted as and comprise a kind of chemical compound, a kind of salt etc.
Any asymmetric carbon atom can exist (R)-, (S)-or (R S)-configuration, is preferably (R)-or (S)-configuration.Therefore chemical compound can exist mixture of isomers or pure isomer form, is preferably enantiomer-pure diastereomer.
The present invention also relates to the possible tautomer of formula I chemical compound.
Low alkyl group preferably comprises 1 to 7 (comprising 7), preferably comprises 1 to 4 atom (comprising 4), and is alkyl straight chain or side chain; Preferably, low alkyl group is for example normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, propyl group such as n-pro-pyl or isopropyl, ethyl or a methyl of butyl.Preferred low alkyl group is methyl, propyl group or the tert-butyl group.
Lower acyl is formoxyl or lower alkylcarbonyl, particularly acetyl group preferably.
Aryl is the bonded aromatic group of valence link with the aromatic ring carbon atom of molecule by being positioned at group.In preferred embodiments; aryl is the aromatic group that 6 to 14 carbon atoms are arranged; phenyl particularly; naphthyl; tetralyl; fluorenyl or phenanthryl; and be unsubstituted or by one or more; preferably can reach three; particularly one or two substituent group replaces; substituent group is selected from amino especially; list or disubstituted amido; halogen; low alkyl group; the low alkyl group that replaces; low-grade alkenyl; low-grade alkynyl; phenyl; hydroxyl; the hydroxyl of etherificate or esterification; nitro; cyano group; carboxyl; the carboxyl of esterification; the alkane ketone group; benzoyl; carbamoyl; N-is single to be replaced or N; N-disubstituted amido formoxyl; amidino groups; guanidine radicals; urea groups; sulfydryl; sulfenyl; lower alkylthio; thiophenyl; phenyl-lower alkylthio; low alkyl group phenyl sulfenyl; the low alkyl group sulfinyl; the phenyl sulfinyl; phenyl-low alkyl group sulfinyl; low alkyl group phenyl sulfinyl; the low alkyl group sulfonyl; phenyl sulfonyl; phenyl-low alkyl group sulfonyl; the low alkyl group phenyl sulfonyl; halogen-low alkyl group sulfydryl; halogen-low alkyl group sulfonyl, for example trifluoromethane sulfonyl group particularly; dihydroxy boryl (B (OH)
2), adjacent C-atom place bonded low-grade alkylidene dioxy base, for example the methylene dioxy base of heterocyclic radical, monocycle or bicyclic heteroaryl and ring.Aryl more preferably is phenyl, naphthyl or tetralyl, can be unsubstituted in each case, also can be to be replaced by one or two substituent group that is selected from halogen, particularly fluorine, chlorine or bromine independently; Hydroxyl; By low alkyl group methyl, the halogen-low alkyl group hydroxyl of trifluoromethyl or phenyl etherificate for example for example; Two adjacent C-atoms are by the bonded low-grade alkylidene of dioxy, methylene dioxy base for example, and low alkyl group is methyl or propyl group for example; Halogen-low alkyl group, for example trifluoromethyl; Hydroxy lower alkyl, for example hydroxymethyl or 2-hydroxyl-2-propyl group; Lower alkoxy-low alkyl group, for example methoxy or 2-methoxy ethyl; Elementary alkoxy carbonyl-low alkyl group, for example methoxyl group-carbonyl methyl; Low-grade alkynyl, for example 1-propinyl; The carboxyl of esterification, particularly elementary alkoxy carbonyl, methoxycarbonyl for example, positive propoxy carbonyl or isopropoxy carbonyl; The single substituted-amino formoxyl of N-, particularly by low alkyl group, the mono-substituted carbamoyl of methyl, n-pro-pyl or isopropyl for example; Amino; Low-grade alkyl amino, for example methylamino; Two-low-grade alkyl amino, for example dimethylamino or diethylamino; Low-grade alkylidene-amino, for example pyrrolidine-1-base or piperidino; Lower oxaalkylene-amino, for example morpholinyl, rudimentary azepine alkylidene-amino, for example piperazine-1-base, acetylamino, for example acetyl-amino or benzoyl-amido; Low alkyl group sulfonyl, for example methyl sulphonyl; Sulfamoyl; Or phenyl sulfonyl.
Cycloalkyl is cyclopropyl, cyclopenta, cyclohexyl or suberyl preferably, and can be unsubstituted or by one or more, particularly one or two be selected from above definition for the substituent group of aryl, most preferably by low alkyl group for example methyl, lower alkoxy for example the substituent group of methoxy or ethoxy or hydroxyl replace, and can be replaced by the oxo base further, or condense and be the benzo ring, for example benzo cyclopenta or benzo cyclohexyl.
Substituted alkyl is alkyl, particularly low alkyl group, preferably methyl as defined above; Can exist one or more, can reach three substituent groups especially, substituent group mainly is selected from halogen particularly fluorine, amino, N-low-grade alkyl amino, N, N-two elementary alkyl amido, N-lower alkane acylamino-, hydroxyl, cyano group, carboxyl, elementary alkoxy carbonyl and phenyl-lower alkoxycarbonyl.Trifluoromethyl is particularly preferred.
Single replacement or disubstituted amido are to be selected from the amino that following group replaces by one or two independently of one another especially: low alkyl group is methyl for example; Hydroxy lower alkyl is the 2-hydroxyethyl for example; The lower alkoxy low alkyl group is methoxy ethyl for example; Phenyl-low alkyl group is benzyl or 2-phenylethyl for example; The lower alkane acyl group is acetyl group for example; Benzoyl; Substituted benzoyl, wherein phenyl be especially by one or more, preferably be selected from nitro, amino, halogen, N-low-grade alkyl amino, N by one or two, the substituent group of N-two elementary alkyl amido, hydroxyl, cyano group, carboxyl, elementary alkoxy carbonyl, lower alkane acyl group and carbamoyl replaces; And phenyl-lower alkoxycarbonyl, wherein phenyl is unsubstituted or especially by one or more, preferably be selected from nitro, amino, halogen, N-low-grade alkyl amino, N by one or two, the substituent group of N-two elementary alkyl amido, hydroxyl, cyano group, carboxyl, elementary alkoxy carbonyl, lower alkane acyl group and carbamoyl replaces; And be preferably the N-low-grade alkyl amino; N-methylamino for example; hydroxy lower alkyl amino; for example 2-hydroxyethyl amino or 2-hydroxypropyl; the lower alkoxy low alkyl group; methoxy ethyl for example; phenyl-low-grade alkyl amino; benzyl amino for example; N; the N-two elementary alkyl amido; N-phenyl lower alkyl-N-low-grade alkyl amino; N; N-two low alkyl group phenyl aminos; low-grade alkane acidyl amino; acetyl-amino for example; or be selected from the substituent group of benzoyl-amido and phenyl-lower alkoxycarbonyl amino group; wherein phenyl is unsubstituted or especially by nitro or amino in each case; perhaps also can be by halogen; amino; the N-low-grade alkyl amino; N, the N-two elementary alkyl amido; hydroxyl; cyano group; carboxyl; elementary alkoxy carbonyl; low-grade alkane acidyl; carbamoyl or amino carbonyl amino replace.Disubstituted amido also is low-grade alkylidene-amino, for example, and pyrrolidine-1-base, 2-oxo-pyrrolidine-1-base or piperidino; Lower oxaalkylene-amino is morpholino or rudimentary azepine alkylidene-amino for example, for example piperazine-1-base or N-substituted-piperazinyl-1-base, for example N methyl piperazine-1-base or N-methoxycarbonyl piperazine-1-base.
Halogen is fluorine, chlorine, bromine or iodine, particularly fluorine, chlorine or bromine particularly.
The hydroxyl of etherificate is C particularly
8-C
20Alkoxyl, for example just-last of the ten Heavenly stems oxygen base, lower alkoxy (preferably), for example methoxyl group, ethyoxyl, isopropoxy or tert-butoxy, phenyl-lower alkoxy, for example benzyloxy, phenoxy group, halogen-lower alkoxy, for example trifluoromethoxy, 2,2,2-trifluoro ethoxy or 1,1,2,2-tetrafluoro ethyoxyl, or contained the lower alkoxy that the monocycle of one or two nitrogen-atoms or bicyclic heteroaryl replace is preferably by imidazole radicals 1H-imidazoles-1-base for example; Pyrrole radicals; Benzimidazolyl is the 1-benzimidazolyl for example; Pyridine radicals is 2-, 3-or 4-pyridine radicals particularly; Pyrimidine radicals is the 2-pyrimidine radicals particularly; Pyrazinyl; Isoquinolyl is 3-isoquinolyl, quinolyl particularly; The lower alkoxy that indyl or thiazolyl replace.
The hydroxyl of esterification is lower alkanoyloxy, benzoyloxy, elementary alkoxy carbonyl oxygen base tert-butoxycarbonyl oxygen base for example especially, or phenyl-lower alkoxycarbonyl oxygen base benzyloxycarbonyl group oxygen base for example.
Esterifying carboxyl group is elementary alkoxy carbonyl particularly, for example tert-butoxycarbonyl, isopropoxy carbonyl, methoxycarbonyl or ethoxy carbonyl, phenyl elementary alkoxy carbonyl or phenyloxycarbonyl.
Alkanoyl is alkyl-carbonyl especially, more particularly low-grade alkane acidyl acetyl group for example.
N-is single to be replaced or N, and N-disubstituted amido formoxyl particularly is independently selected from low alkyl group, phenyl-low alkyl group and hydroxy lower alkyl or low-grade alkylidene, oxa--low-grade alkylidene or the randomly substituent group of the substituted azepine-low-grade alkylidene of nitrogen-atoms replacement endways by one or two.
The monocycle or the bicyclic heteroaryl that contain zero, one, two or three theheterocyclic nitrogen atoms and zero or oxygen atom and a zero or a sulphur atom, group is unsubstituted or single replacement or polysubstituted in each case, refer to the heterocyclic moiety of the unsaturated part in the bonded ring of remainder of heteroaryl and formula I molecule, and preferably encircle, in bonded ring, but randomly also be in any condensed ring, the hetero atom of the selected group from nitrogenous, oxygen and sulfur of at least one carbon atom replaces; Wherein coupling collar preferably has 5-12, and 5 or 6 annular atomses are more preferably arranged; And can be unsubstituted or by one or more, particularly one or two be selected from the group aryl substituent of above definition, most preferably by low alkyl group for example methyl, lower alkoxy for example the substituent group of methoxy or ethoxy or hydroxyl replace.Preferably monocycle or bicyclic heteroaryl are selected from the 2H-pyrrole radicals, pyrrole radicals, imidazole radicals, benzimidazolyl, pyrazolyl, indazolyl, purine radicals, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, the 4H-quinolyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoline quinoline base, quinazolyl, quinolyl, pteridyl, the indolizine base, the 3H-indyl, indyl, isoindolyl, azoles base, different azoles base, thiazolyl, isothiazolyl, triazolyl, tetrazole radical, the furazan base, benzo (d) pyrazolyl, thienyl and furyl.More preferably monocycle or bicyclic heteroaryl, it is selected from pyrrole radicals, imidazole radicals, for example 1H-imidazole radicals-1-base, benzimidazolyl, for example 1-benzimidazolyl, indazolyl, particularly 5-indazolyl, pyridine radicals, particularly 2-, 3-or 4-pyridine radicals, pyrimidine radicals, particularly 2-pyrimidine radicals, pyrazinyl, isoquinolyl, particularly 3-isoquinolyl, quinolyl, particularly 4-or 8-quinolyl, indyl, particularly 3-indyl, thiazolyl, benzo (d) pyrazolyl, thienyl and furyl.Therefore in an embodiment preferred of the present invention, pyridine radicals is replaced by hydroxyl on the ortho position of nitrogen-atoms, has the corresponding part tautomeric forms of 2-ketone of pyrimidine-(1H) at least.In another preferred embodiment, pyrimidine radicals is to be replaced by hydroxyl on 2 and 4 two positions, therefore has several tautomeric forms, for example, and pyrimidine-(1H, 3H) 2,4-diketone.
Heterocyclic radical be have especially be selected from nitrogenous, oxygen and methylthio group one or two heteroatomic five, six or the seven membered heterocyclic system, can be unsaturated or saturated wholly or in part, and be do not replace or especially by low alkyl group for example methyl, phenyl-low alkyl group for example benzyl, oxo or heteroaryl for example the 2-piperazinyl replace; Heterocyclic radical particularly 2-or 3-pyrrolidinyl, 2-oxo-5-pyrrole ratio is coughed up alkyl, piperidyl, N-benzyl-4-piperidyl, N-low alkyl group-4-piperidyl, N-low alkyl group-piperazinyl, morpholinyl for example 2-or morpholinyl, 2-oxo-1H-azepine -3-base, 2-tetrahydrofuran base or 2-methyl isophthalic acid, 3-dioxolanyl-2-base.
Salt is the officinal salt of formula I chemical compound especially.
These salt for example form with acid-addition salts, preferably by organic acid or mineral acid and have the salt, particularly officinal salt of the formula I compound formation of basic nitrogen atom.The mineral acid that is fit to is that for example, halogen acid is hydrochloric acid, sulphuric acid or phosphoric acid for example.The organic acid that is fit to is a carboxylic acid for example, phosphonic acids, sulfonic acid or sulfamic acid, acetic acid for example, propanoic acid, sad, capric acid, dodecanoic acid, glycolic, lactic acid, fumaric acid, succinic acid, adipic acid, 1,5-pentanedicarboxylic acid., suberic acid, Azelaic Acid, malic acid, tartaric acid, citric acid, aminoacid is glutamic acid or Aspartic Acid for example, maleic acid, hydroxymaleic acid, citraconic acid, naphthenic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, the 4-aminosallcylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, Loprazolam or ethane sulfonic acid, the 2-hydroxyethanesulfonic acid, ethane-1, the 2-disulfonic acid, benzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2,1, the 5-naphthalenedisulfonic acid, 2-, 3-, the 4-toluene sulfonic acide, methane sulphuric acid, ethane sulphuric acid, dodecane sulphuric acid, N-cyclohexyl sulfamic acid, the N-methyl-, the N-ethyl-or N-propyl group-sulfamic acid, or other organic Bronsted acid, for example ascorbic acid.
When having negative charge group such as carboxyl or sulfo group, can with alkali salify, for example slaine or ammonium salt, for example alkali metal salt or alkali salt, for example sodium, potassium, magnesium or calcium salt, with ammonia or suitable organic amine uncle's monoamine for example, the ammonium salt that becomes as triethylamine or three (2-ethylol amine); Or with heterocyclic bases for example N-ethylpiperidine or N, the salt that N '-lupetazin becomes.
When having basic group or acidic-group in same molecule, formula I chemical compound also can form inner salt.
For isolated or purified, also may use not officinal salt, for example picrate or perchlorate.Have only officinal salt or its free chemical compound (wherein using) just to can be used for treatment, so they are preferred with the form of pharmaceutical preparation.
Noval chemical compound and its salt of considering free form (comprise that also those can be as the salt of intermediate, for example at the noval chemical compound purification or the salt in identifying) substantial connection, when suitable and favourable, any noval chemical compound that relates to also can be understood to include corresponding salt in the context.
Chemical compound in formula I scope and preparation method thereof is disclosed among the WO 04/005281 that is published on January 15th, 2004, and this paper quotes the reference as the application.Preferred chemical compound is 4-methyl-3-[[4-(3-pyridine radicals)-2-pyrimidine radicals] amino]-N-[5-(4-methyl isophthalic acid H-imidazoles-1-yl)-3-(trifluoromethyl) phenyl] Benzoylamide.
Compositions of the present invention comprises the kinase whose chemical compound of inhibition RAF, function is the serine/threonine kinase of map kinase signal transduction path, these combination products are used for the map kinase signal transduction path and are the disease treatment of feature unusually, for example, and as the proliferative disease of certain cancers.
The RAF inhibitor is for example in the following analysis with the IC of 0.05mmol/L to＞4.0mmol/L
50Value suppresses wild type C-Raf, and/or with the IC of 0.08mmol/L to＞4.0mmol/L
50The chemical compound of value mutation inhibiting type B-Raf (V599E).
The RAF kinase activity assay: active B-Raf, C-Raf and V599EB-Raf human body sequence protein use baculovirus expression system purification from insect cell.The use of Raf inhibitory action scribbles IkB-α and tests with 96 hole microwell plates of Superblock blocking-up.IkB-α uses phosphorylation-IkB-alpha specific antibody (cellular signal transduction #9246), the anti-mice IgG alkali phosphatase (Pierce#31320) of coupling secondary antibodies, alkaline phosphatase substrate in the phosphorylation of serine 36, (Promega #S101) detects ATTOPHOS.
Suitable R AF inhibitor comprises, for example:
Disclosed chemical compound, for example formula II chemical compound among the WO 00/09495 that announced on February 24th, 2000:
Wherein
R is 0 to 2;
N is 0 to 2;
M is 0 to 4;
A, B, D and E are N or CH independently of one another, and condition is that no more than two of these groups are N; G is a low-grade alkylidene ,-CH
2-O-,-CH
2-S-,-CH
2-NH-, oxa-(O-), thia (S-) or imido grpup (NH-), or the low-grade alkylidene that is replaced by acyloxy or hydroxyl;
Q is a low alkyl group, particularly methyl;
R is H or low alkyl group;
X is that imido grpup, oxa-or sulfur are assorted;
Y is a low alkyl group, or particularly aryl, heteroaryl or cycloalkyl unsubstituted or that replace; And
Z is amino, the single replacement or disubstituted amido, halogen, alkyl, substituted alkyl, hydroxyl, the hydroxyl of etherificate or esterification, nitro, cyano group, carboxyl, the carboxyl of esterification, alkanoyl, carbamoyl, N-is single to be replaced or N, N-disubstituted amido formoxyl, amidino groups, guanidine radicals, sulfydryl, sulfo group, thiophenyl, phenyl-lower alkylthio, alkyl sulfur-base, phenyl-low alkyl group sulfinyl, phenyl-low alkyl group sulfinyl, the alkyl-phenyl sulfinyl, phenyl sulfonyl, phenyl-lower alkane sulfonyl or benzene sulfonamide acyl group, if and exist more than a group Z (m 〉=2), then substituent group Z is identical or different;
And wherein the valence link represented of wave can be singly-bound or two key; Or the N-oxide of mentioned chemical compound, wherein one or more N atoms carry oxygen atom; Or its salt.
Particularly preferably be (the 4-tert-butyl group-phenyl)-(4-pyridin-4-yl methyl-isoquinolyl-1)-amine.
-other RAF inhibitor comprises and is selected from [4,7 ']-chemical compound of two isoquinolyl-1s-4-(tert-butyl group-phenyl)-amine, (the 4-tert-butyl group-phenyl)-(4-quinazoline-6-base-isoquinolyl-1)-amine and [4,7 ']-two isoquinolyl-1-(the 2-tert-butyl group-pyrimidine-5-yl)-amine.
-other RAF inhibitor comprises disclosed chemical compound, for example formula III chemical compound among the WO 04/110452 that December in 2004 announced on the 23rd:
Wherein:
R
1Be phenyl or heteroaryl; And
R
2Be phenyl;
Perhaps its N-oxide or officinal salt.
About compound III, when mentioning that substituent group is for example when alkyl, alkoxyl, alkylamine, alkylthio group etc., term " rudimentary " expression has at the most 7 and comprise 7 of maximums, especially 1 to 4 and comprise the group of 4 carbon atoms of maximum at the most, and described group is unbranched or by the branching one or many.
About compound III, low alkyl group, lower alkoxy, list-or two-low-grade alkyl amino, lower alkylthio and other have moieties C especially in the substituent group of moieties
1-C
4Alkyl, for example normal-butyl, sec-butyl, the tert-butyl group, n-pro-pyl, isopropyl, methyl or ethyl.Except as otherwise noted, otherwise described alkyl substituent is unsubstituted or by halogen, hydroxyl, nitro, cyano group, lower alkoxy, C
3-C
7Cycloalkyl, amino or single-or two-low-grade alkyl amino replace.
About compound III, halogen-low alkyl group, halogen-lower alkoxy, halogen-lower alkylthio etc. be meant have moieties, wherein moieties is replaced the substituent group that replaces to fully by the halogen list.Halogen-low alkyl group, halogen-lower alkoxy, halogen-lower alkylthio etc. are included within the low alkyl group of replacement, the lower alkoxy of replacement, the lower alkylthio of replacement etc.
About compound III, halogen is fluorine, chlorine, bromine or iodine especially, more particularly fluorine, chlorine or bromine, particularly fluorine.
About compound III, phenyl generally is unsubstituted phenyl or the phenyl that replaced by 1-5, preferred 1 or 2 substituent group.Suitable substituent group includes but not limited to amino; single-or the amino (wherein low-grade alkyl substituent can be unsubstituted or further as above those listed substituent groups of alkyl be replaced) that replaces of two-low alkyl group; halogen; low alkyl group; the low alkyl group that replaces; hydroxyl; lower alkoxy; the lower alkoxy that replaces; nitro; cyano group; sulfydryl; lower alkylthio; halogen-lower alkylthio; heterocyclic radical; heteroaryl; the heterocyclic radical alkyl; heteroaryl alkyl; low-grade alkane acidyl; carbamoyl and N-list-or N; the carbamoyl that N-two-low alkyl group replaces, wherein low-grade alkyl substituent can be unsubstituted or further be replaced.
In compound III, be the R of phenyl
1Especially unsubstituted phenyl or by one or more substituent groups, preferred three at the most, the especially phenyl that substituent group replaces.To R
1The substituent group that phenyl is even more important comprises amino, list-or the lower alkylthio of lower alkoxy, nitro, cyano group, sulfydryl, lower alkylthio and the replacement of the low alkyl group of two-low-grade alkyl amino (wherein alkyl is unsubstituted or substituted), halogen, low alkyl group, replacement, hydroxyl, lower alkoxy, replacement.
R for phenyl
1Especially unsubstituted phenyl or the phenyl that is replaced by one or two identical or different substituent group, described substituent group is selected from halogen, especially fluorine or chlorine; Low alkyl group, especially methyl, ethyl, propyl group or the tert-butyl group; Halogen-low alkyl group, especially trifluoromethyl; Hydroxyl; Lower alkoxy, especially methoxy or ethoxy; Halogen-lower alkoxy, trifluoromethoxy or 1,1,2 for example, 2-tetrafluoro ethyoxyl; More particularly by the phenyl of a substituent group replacement, described substituent group is selected from low alkyl group unsubstituted or that replace, especially methyl, halogen-low alkyl group, for example trifluoromethyl, the unsubstituted or lower alkoxy that replaces, especially methoxyl group and halogen-lower alkoxy, especially trifluoromethoxy.
In compound III, be the R of phenyl
2Generally be unsubstituted phenyl ring or the phenyl ring that preferably replaced by one or more substituent groups, preferred three at the most, especially one or two substituent group.Substituent group is especially amino, single-or the amino that replaces of two-low alkyl group (wherein alkyl is unsubstituted or is further replaced; especially replaced by halogen or lower alkoxy), halogen, the unsubstituted or low alkyl group that replaces, lower alkoxy, hydroxyl, nitro, cyano group, low-grade alkane acidyl, carbamoyl, N-unsubstituted or that replace be single-or N, carbamoyl, sulfydryl, lower alkylthio and halogen-lower alkylthio that N-two-low alkyl group replaces.
R for phenyl
2Be preferably the phenyl that is replaced by one or two identical or different substituent group, described substituent group is selected from halogen, especially fluorine or chlorine; Single-or two-low alkyl group amino, the especially dimethylamino or the diethylamino that replace; Low alkyl group, especially methyl or ethyl; Halogen-low alkyl group, especially difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2-tetrafluoro ethyl; Lower alkoxy, especially methoxy or ethoxy; Halogen-lower alkoxy, especially difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy or 1,1,2,2-tetrafluoro ethyoxyl; Lower alkylthio, for example methyl mercapto; Halogen-lower alkylthio, for example difluoro methyl mercapto, trifluoromethylthio, 2,2,2-trifluoro ethylmercapto group or 1,1,2,2-tetrafluoro ethylmercapto group.R for phenyl
2More particularly by the phenyl of one or two identical or different substituent group replacement, described substituent group is selected from low alkyl group that unsubstituted or halogen replaces, unsubstituted or lower alkoxy that halogen replaces, unsubstituted or lower alkylthio and halogen, especially fluorine or chlorine that halogen replaces.
About compound III, heteroaryl especially comprises 1 to 3 heteroatomic 5 to 7 yuan of aromatic ring that are selected from N, O and S.Heteroaryl be unsubstituted or by one or more, especially one to three, for example an identical or different substituent group replaces.Important substituent group on the heteroaryl is that those are selected from following substituent group: halogen, for example fluorine or chlorine; Single-or the amino that replaces of two-low alkyl group, wherein alkyl is unsubstituted or by halogen, hydroxyl, nitro, cyano group, lower alkoxy, C
3-C
7Cycloalkyl, heterocyclic radical or heteroaryl replace; Low alkyl group, for example methyl or ethyl; Halogen-low alkyl group, for example trifluoromethyl; Lower alkoxy, for example methoxy or ethoxy; Halogen-lower alkoxy, for example trifluoromethoxy; Lower alkylthio, for example methyl mercapto; Halogen-lower alkylthio, for example trifluoromethylthio; Heteroaryl; Heteroaryl-low-grade alkylidene; Heterocyclic radical or heterocyclic radical-low-grade alkylidene.
Heteroaryl-low-grade alkylidene and heterocyclic radical-low-grade alkylidene are formula het-C
1-C
4-alkylidene-substituent group, wherein het is heteroaryl or heterocyclic radical.
-other RAF inhibitor comprises disclosed chemical compound, for example formula IV chemical compound among the WO 04/080464 that JIUYUE in 2004 announced on the 23rd:
Wherein
R is 0 to 2;
N is 0 to 2;
M is 0 to 4;
Each is N or CH independently of one another for A, B, D, E and T, and condition is that at least one but no more than three are N among A, B, D, E and the T;
G be low-grade alkylidene ,-CH
2-O-,-CH
2-S-,-CH
2-NH-,-SO
2-, oxa-(O-), thia (S-) or-NR-, or the low-grade alkylidene that is replaced by acyloxy, oxo, halogen or hydroxyl;
Q is a low alkyl group, particularly methyl;
R is H or low alkyl group;
X be Y ,-N (R)-, oxa-or sulfenyl; Preferably-NH-;
Y is H, unsubstituted or the low alkyl group, aryl, heteroaryl or the cycloalkyl unsubstituted or that replace that replace; And
Z is amino, the single replacement or disubstituted amido, halogen, alkyl, substituted alkyl, hydroxyl, the hydroxyl of etherificate or esterification, nitro, cyano group, carboxyl, the carboxyl of esterification, alkanoyl, carbamoyl, N-is single to be replaced or N, N-disubstituted amido formoxyl, amidino groups, guanidine radicals, sulfydryl, sulfonic group, thiophenyl, phenyl-lower alkylthio, the alkyl phenyl sulfenyl, the phenyl sulfinyl, phenyl-low alkyl group sulfinyl, the alkyl-phenyl sulfinyl, phenyl sulfonyl, phenyl-lower alkane sulfonyl or benzene sulfonamide acyl group, if and exist more than a group Z (m 〉=2), then substituent group Z is identical or different;
Or its N-oxide or officinal salt.
-other RAF inhibitor comprises disclosed chemical compound, for example formula V chemical compound among the PCT/EP2004/010688 that JIUYUE in 2004 submitted on the 24th:
Wherein
R is 0-2;
N is 0-2;
M is 0-4;
J is aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, wherein
Aryl is the aromatic radical with 6-14 carbon atom, for example phenyl, naphthyl, fluorenyl and phenanthryl; Heteroaryl is for containing 4-14, special 5-7 annular atoms, wherein 1,2 or 3 atoms are independently selected from N, the aromatic radical of S and O, furyl for example, pyranose, pyridine radicals, 1,2-, 1,3-and 1, the 4-pyrimidine radicals, pyrazinyl, triazine radical, triazolyl, azoles base, quinazolyl, imidazole radicals, pyrrole radicals, different azoles base, isothiazolyl, indyl, iso-dihydro-indole-group, quinolyl, isoquinolyl, purine radicals, the cinnolines base, 1, the 5-phthalazinyl, the 2 base, benzopyranyl, purine radicals, thianthrene group, xanthyl, acridinyl, carbazyl and phenazinyl;
Cycloalkyl is for having 3-8, the saturated cyclic group of preferred 5-6 annular atoms, for example cyclopropyl, cyclopenta and cyclohexyl;
Heterocyclylalkyl is individual for having 3-8, preferred 5-6 annular atoms, and wherein said annular atoms contains 1,2 or 3 the saturated cyclic group that independently is selected from the atom of N, S and O, for example piperidyl, piperazinyl, imidazolidinyl, pyrrolidinyl and pyrazolidinyl;
Q is the substituent group on 1 or 2 carbon atom, is selected from following group: halogen, the unsubstituted or low alkyl group that replaces ,-OR
2,-SR
2,-NR
2,-NRS (O)
2N (R)
2,-NRS (O)
2R ,-S (O) R
2,-S (O)
2R
2,-OCOR
2,-C (O) R
2,-CO
2R
2,-NR-COR
2,-CON (R
2)
2,-S (O)
2N (R
2)
2, cyano group, TMS, the unsubstituted or aryl that replaces, the unsubstituted or heteroaryl that replaces, that for example replace or unsubstituted imidazole radicals and replace or unsubstituted pyridine base, the unsubstituted or cycloalkyl that replaces, the unsubstituted or Heterocyclylalkyl that replaces, that for example replace or unsubstituted piperidyl, replacement or unsubstituted hydroxy piperidine azoles base (piperazolyl), replace or unsubstituted THP trtrahydropyranyl and replace or unsubstituted azetidinyl ,-C
1-4Alkyl-aryl ,-C
1-4Alkyl-heteroaryl ,-C
1-4The amino of alkyl-heterocyclic radical, amino, list-or two-replace;
R is H or low alkyl group;
R
2For unsubstituted or the alkyl that replaces, the unsubstituted or cycloalkyl that replaces, phenyl ,-C
1-4Alkyl-aryl ,-C
1-4Alkyl-heteroaryl or-C
1-4Alkyl-Heterocyclylalkyl;
X be Y ,-N (R)-, oxa-, sulfo-, sulfone, sulfoxide, sulfonamide, amide or ureylene, preferred-NH-;
Y is hydrogen, low alkyl group, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted cycloalkyl or replacement or unsubstituted Heterocyclylalkyl;
Z is amino, single-or two-substituted-amino, halogen, alkyl, the alkyl that replaces, hydroxyl, the hydroxyl of etherificate or esterification, nitro, cyano group, carboxyl, the carboxyl of esterification, alkanoyl, carbamoyl, the N-list-or N, N-disubstituted amido formoxyl, amidino groups, guanidine radicals, sulfydryl, sulfo group, thiophenyl, phenyl-lower alkylthio, alkyl sulfur-base, the phenyl sulfinyl, the phenyl lower alkyl sulfinyl, the alkyl phenyl sulfinyl, phenyl sulfonyl, phenyl-lower alkane sulfonyl or alkyl phenyl sulfonyl, if and wherein exist above a group Z (〉=2), then substituent group Z is identical or different;
The perhaps N-oxide of described chemical compound, wherein one or more N atoms have oxygen atom;
Perhaps its officinal salt.
Under every kind of situation of the quoted passage of the patent application that above provides, this paper introduce relate to this chemical compound theme as a reference.Comprised be equally its officinal salt, corresponding raceme, diastereomer, enantiomer, tautomer and more than the corresponding crystal modification of compound (if existence) of coming into the open, the solvate that for example has been disclosed, hydrate and polymorph.The chemical compound that in combination product of the present invention, is used as active component respectively as citing document in institute retouch and be prepared and use.As mentioned more than the combination product of two kinds of independent active component equally within the scope of the invention, promptly pharmaceutical combination product within the scope of the present invention can comprise three kinds of active component or more.
According to unique discovery of the present invention, it provides
1. pharmaceutical combination product, it comprises:
A) the pyrimdinyl-amino benzamide compounds of formula (I); With
B) at least a RAF inhibitors of kinases.
2. treatment or prevention need the method for the proliferative disease in its individuality, comprise to described individuality for example use jointly simultaneously or successively the formula I of administering therapeutic effective dose the pyrimdinyl-amino benzamide compounds and for example as above disclosed RAF inhibitors of kinases.
The example of proliferative disease comprises, for example tumor, psoriasis, restenosis, scleroderma and fibrosis.
3. be used for as above 2) defined method as above 1) defined pharmaceutical combination product.
As above 1) defined pharmaceutical combination product is used for preparation above 2) medicine that uses of defined method.
The purposes of combination product of the present invention in appointed method above can animal test method and clinical in, for example according to being confirmed in the method described below.
The commercial packing of the combination product that contains above or hereinafter describe.
A. combined therapy
Suitable clinical research for example is, the opening of carrying out in the proliferative disease patient, the research of dosage escalation.This research has confirmed the synergism of combination product active component of the present invention especially.Advantageous effect to psoriasis or multiple sclerosis can directly be measured by these results of study known to those skilled in the art.These researchs are particularly suitable for relatively using the effect of monotherapy of active component and the effect of invention combination product.Preferably, the dosage escalation of composition (a) is until reaching maximum tolerated dose, and composition (b) is used with fixed dosage.Perhaps, composition (a) is used with fixed dosage, the dosage escalation of composition (b).Every patient's every day or accept the dosage of composition (a) discontinuously.Can in this class research, measure the treatment effectiveness, for example in 12,18 or 24 week backs by per 6 weeks to symptom fractional evaluation carry out.
Using of pharmaceutical combination product of the present invention not only reaches advantageous effects, synergistic therapeutic effect for example, for example aspect the progress of alleviation, delay or inhibition symptom, amazing favourable influence is also further arranged, for example, with the single therapy method of only using a kind of active constituents of medicine that uses in the combination product of the present invention still less side effect is arranged relatively, quality of life improves or mortality rate descends.
Further benefit is that combination product of the present invention has used the more active component of low dosage, and for example, required dosage is not only littler but also medicine frequency is lower, can reduce the incidence rate or the degree of side effect.This hope and requirement with the patient that will treat is consistent.
Term " is used " jointly or " combined administration " or similar literal used herein are meant and comprise that selected therapeutic component uses for a patient, and expection comprises therapeutic scheme, and composition needn't be used with identical route of administration or identical time in therapeutic scheme.
An object of the present invention is to provide comprise the co-therapy effective dose at or the pharmaceutical composition of the present invention combination of prevention proliferative disease.In this compositions, composition (a) and (b) can be together, a kind of formerly a kind of in the back or in the unit dosage forms of a combination or two independent unit dose shape types, use respectively.Unit dosage forms can also be fixed combination.
The pharmaceutical composition of for composition (a) and (b) using respectively or using with fixed combination, promptly contain at least two kinds of combined partner capables (a) and single lid human relations compositions (b), can prepare by mode known per se according to the present invention, these compositionss are suitable for enteral and use for example oral or rectal administration, comprise that the people uses for mammal (homoiothermic animal) outward with intestinal, only comprise at least a pharmacologically active combined partner capable for the treatment of effective dose, for example, specified as mentioned, or pharmaceutically acceptable with one or more, particularly be suitable in the intestinal or the outer application carrier of intestinal or diluent are used in combination.
Suitable pharmaceutical composition for example comprises from about 0.1% to about 99.9%, preferably from about 1% to about 60% active component.Be used for combined therapy in intestinal or the pharmaceutical preparation of using outside the intestinal be, for example, such as the unit dosage forms of coated tablet, sheet, capsule or suppository or ampoule.If not special indicating, these all are to prepare in mode known per se, for example by traditional mixing, granulation, sugar coating, dissolving or freeze dried method.The unit content that should be appreciated that the combined partner capable that comprises in the single dosage that is included in each dosage form does not need self to constitute effective dose, because essential effective dose can reach by using a plurality of dosage units.
Especially, the treatment effective dose of each of the combined partner capable of combination product of the present invention can simultaneously or be used with any order successively, and composition can be used individually or with fixed combination.For example, method according to prevention of the present invention or treatment proliferative disease can comprise (i) first kind of composition (a) using with the form of free form or officinal salt, reach (ii) composition (b) using with free form or pharmaceutical acceptable salt, successively use simultaneously or with any order, with the co-therapy effective dose, preferably with cooperative effective quantity, for example with dosage or be interrupted dosage and use every day corresponding to this paper description amount.Every kind of combined partner capable of combination product of the present invention can be during therapeutic process different time respectively or use with fractionated dose or independent combining form simultaneously.In addition, term is used and is also comprised that use changes into the prodrug of the combined partner capable of combined partner capable itself in vivo.Therefore the present invention can be regarded as and comprises simultaneously or all schemes of alternating treatment, and term administering " can do corresponding understanding.
In the combination product of the present invention the effective dose of used each combined partner capable can be according to used specific compound or pharmaceutical composition, method of application, the disease of being treated, changed by the sanatory order of severity.Therefore, can come according to the various factors of kidney that comprises route of administration and patient and liver function the dosage of combination product of the present invention is selected.Common doctor, clinicist can easily determine and provide the effective dose that is used to alleviate, strike back or suppress the required single active component of disease process.The optimum precision that acquisition is positioned at the activity component concentration that can produce effectiveness and can the toxigenicity scope needs a kind of based on the scheme of target site to the kinetics of active component availability.
Composition (a) or dosage every day (b) will change with multiple factor certainly, for example selected compounds, the special disease that will treat and the effect of wanting.Usually, composition (a) with every day dosage serve as the order of magnitude of about 0.03-5mg/kg/d, particularly 0.1-5mg/kg/d, 0.1-2.5mg/kg/d for example in the mode of single dose or fractionated dose, can realize satisfied result.Composition (a) and composition (b) can be used by any classical pathway, and be in the intestinal, for example oral especially, for example with the form of tablet, capsule, drinkable solutions; Or parenteral mode, for example form of injection solution or suspension.The suitable Orally administered unit dosage form that is suitable for comprises about 0.02 to 50mg active component, and common 0.1 to 30mg, and composition (a) or (b) for example is together with one or more pharmaceutically acceptable diluents or carrier.
Composition (b) can 0.5-1000mg dosage range every day be applied to human body.Suitable be used for the active component that oral unit dosage forms comprises about 0.1-500mg, together with one or more pharmaceutically acceptable diluents or carrier.
Using not only of pharmaceutical combination product of the present invention can produce advantageous effect, possesses synergistic for example, for example suppress the unadjusted proliferation function of hematology stem cell or slow down for example progress of CML or AML or tumor growth of leukemia, amazing advantageous effect is also further arranged, for example with use combination product of the present invention in a kind of single therapy method in the active constituents of medicine that uses compare and have less side effect, improved quality of life or reduced mortality rate.
Further benefit is that combination of the present invention can be used the more active component of low dosage, and for example, required dosage is not only littler but also medicine frequency is lower, perhaps uses so that reduce the incidence rate of side effect.This hope and requirement with the patient that will treat is consistent.
B. the disease that will treat
Term " proliferative disease " includes but not limited to tumor, psoriasis, restenosis, scleroderma and fibrosis.
Term the hematology cancerate, refer in particular to leukemia, particularly express those leukemia of Bcr-Abl, c-Kit or Flt-3, also include but not limited to chronic granulocytic leukemia and acute lymphoblastic leukemia (ALL), particularly positive acute lymphoblastic leukemia (Ph+ALL) of Philadelphia chromosome and STI571 resistance leukemia.
Term " solid tumor disease " refers in particular to ovarian cancer, breast carcinoma, colon cancer and general gastrointestinal cancer, cervical cancer, pulmonary carcinoma, for example small cell lung cancer and nonsmall-cell lung cancer, head and neck cancer, bladder cancer, carcinoma of prostate or Kaposi sarcoma.
According to the combination that suppresses the protein tyrosine kinase activity that mentioned protein kinase activity, particularly context mention of the present invention, can be used for the treatment of protein kinase dependence disease.The protein kinase dependence disease is to refer in particular to proliferative disease, preferred optimum or malignant tumor (for example a plurality of tumors and the leukemia of kidney, liver, adrenal gland, bladder, mammary gland, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid carcinoma, sarcoma, glioblastoma and head and cervical region) particularly.They can bring disappearing of tumor, and prevent the formation of neoplasm metastasis and the growth of transfer (also claiming micrometastasis).In addition, they can be used for epithelium hyper-proliferative (for example, psoriasis), prostatic hyperplasia, and neoplasia, particularly epithelial cell feature, for example breast carcinoma.Also may use combination product of the present invention in several diseases of immune system scope or relate to the treatment of diseases of individual tyrosine protein kinase especially; In addition, combination product of the present invention also can be used for relating to the signal conduction by at least a, be selected from the kinase whose maincenter of those tyrosine protein matter specifically mentioned or the treatment of peripheral nervous disease especially.
In chronic granulocytic leukemia (CML), mutual equilibrated chromosome translocation produces the BCR-ABL heterozygous genes in the hematology stem cell (HSCs).The latter carcinogenic Bcr-Abl that encodes condenses albumen.Yet ABL is coded in the protein tyrosine kinase of the height regulation and control that play a major role in regulating cell propagation, adhesion and the apoptosis, the BCR-ABL fusion gene is encoded to structure and activates kinases, can transform HSC with generation present imbalance the clonal expansion effect, be adsorbed in the phenotype that the bone marrow interstital ability reduces, reduced to make it day by day gather mutation stimulated cells apoptosis is responded into more pernicious degeneration.The granulocyte that obtains can not develop into sophisticated lymphocyte and be discharged in the circulation, causes the mature cell shortage and has increased the susceptibility that infects.The ATP-competitive inhibitor of having described Bcr-Abl can prevent kinase activator mitosis and anti-apoptotic approach (for example P-3 kinases and STAT5), causes BCR-ABL phenotype cell death and effective treatment to CML is provided whereby.Therefore combination product of the present invention is particularly suitable for relating to the treatment of diseases, particularly leukemia of its overexpression, for example CML or ALL leukemia.
The RAF kinase inhibition character of combination product of the present invention makes their useful as therapeutics, being used for the treatment of with the map kinase signal path is the proliferative disease of feature unusually, particularly many is the cancer of feature with RAF kinases overexpression or the kinase whose activated mutant of RAF, the melanoma that for example has the B-RAF of sudden change, especially wherein Tu Bian B-RAF is the melanoma of V599E mutant.The present invention also provide with combined therapy of the present invention other with the map kinase signal path be unusually the disease of feature, particularly wherein the disease of B-RAF sudden change, for example have a method of the benign nevus (Nevimoles) of the B-RAF of sudden change.
Usually, the disease that is feature with unusual map kinase signal path is a proliferative disease, particularly increases to the cancer of feature with the RAF kinase activity, for example crosses expression wild type B-or C-RAF kinases, or express activated sudden change RAF kinases, the kinase whose disease of B-RAF of for example suddenling change.The kinase whose cancer of RAF that wherein detects sudden change comprises melanoma, colorectal carcinoma, ovarian cancer, glioma, adenocarcinoma, sarcoma, breast carcinoma and hepatocarcinoma.The B-RAF kinases that suddenlys change in many melanoma is especially ubiquitous.
According to the present invention, get the diseased tissue sample on one's body from the patient, for example result of biopsy or excision, and test is to determine to organize the RAF kinases that whether has produced sudden change, for example the wild type RAF kinases of Tu Bian B-RAF kinases or overexpression, for example wild type B-or C-RAF kinases.If test shows produced sudden change RAF kinases or excessively produced the RAF kinases in diseased tissue, the patient can treat by the RAF inhibitor compound described herein of using effective RAF amount of suppression.
Further according to the present invention, it is the purposes that the present invention's combination described herein is used to prepare treatment melanoma medicine, the melanoma tissue that comprises (a) test patient is to determine whether the melanoma wild type RAF kinases of having expressed the RAF kinases of sudden change or overexpression, (b) if finding the melanoma excessive tissue has expressed wild type RAF kinases or expressed activated sudden change B-RAF kinases, then use the combined therapy patient of the present invention of effective RAF kinase inhibition amount.
But,, also be possible then with RAF kinase inhibiting compound downward modulation map kinase signal transduction path if other kinases are reasons of excessive signal conduction in the approach in cascade reaction.Therefore, the invention further relates to excessive signal conduction in the map kinase signal transduction path is feature, but not kinase whose activated mutant of RAF or overexpression are the treatment of diseases of the cause of disease.
Combination product of the present invention mainly suppresses vessel growth, therefore for example effectively resisted blood vessel generation with imbalance, the disease that causes by the eye neovascularization particularly, retinopathy particularly, for example diabetic renal papillary necrosis or treating senile maculopathy, psoriasis, hemangioblastoma, hemangioma for example, the mesangial cell proliferative disorders, for example chronic or acute nephropathy, diabetic nephropathy for example, malignant nephrosclerosis disease, thrombotic microangiopathy syndrome or transplant rejection, or inflammatory nephropathy especially, glomerulonephritis for example, membrano proliferative glomerulonephritis especially, haemolysis-uremia's property syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, from immune disease, diabetes, endometriosis, chronic asthma, reach neoplastic disease (solid tumor especially, comprise that also leukemia and other hematologys cancerate), breast carcinoma especially for example, colon cancer, pulmonary carcinoma (small cell lung cancer especially), carcinoma of prostate or Kaposi sarcoma.Combination product of the present invention suppresses tumor growth, and is particularly suitable for suppressing the transfer propagation and the micrometastasis growth of tumor.
The present invention relates to treat the method for myeloma, particularly the traditional chemical therapy is had the myeloma of resistance.Term used herein " myeloma " relates to the tumor of being made up of the cell of the normal type of finding in bone marrow.The secretion that term used herein " multiple myeloma " means with multiple myeloma kitchen range and M composition (monoclonal immunoglobulin segment) is the plasmacytic dispersivity malignant growth of feature, is accompanied by the osteolytic lesion that blazons that causes osteodynia, pathologisch Bruch, hypercalcemia and the normal normocytic anemia of erythrocyte color.The multiple myeloma use is traditional to be difficult to cure with chemical therapeutic method high dose.The present invention relates to treat myeloma, the particularly method of the myeloma of anti-traditional chemical Therapeutic Method.
Claims (10)
1. pharmaceutical combination product, it comprises
A) the pyrimidylaminobenzamderivatives chemical compound of formula (I); With
B) at least a RAF inhibitors of kinases.
2. treatment or prevention need the method for the proliferative disease in its individuality, comprise to described individuality for example using jointly simultaneously or the successively at least a RAF inhibitors of kinases of administering therapeutic effective dose and the pyrimidylaminobenzamderivatives chemical compound of formula (I).
3. be used for pharmaceutical combination product according to claim 1 according to the method for claim 2.
4. be used to prepare the drug regimen according to claim 1 of the medicine for the treatment of proliferative disease.
5. according to the pharmaceutical combination product of claim 1, composition wherein a) is selected from 4-methyl-3-[[4-(3-pyridine radicals)-2-pyrimidine radicals] amino]-N-[5-(4-methyl isophthalic acid H-imidazoles-1-yl)-3-(trifluoromethyl) phenyl] Benzoylamide.
6. the purposes of the method for claim 2 or claim 4, proliferative disease wherein is a myeloma.
7. claim 2,3 or 6 method or the purposes of claim 4 or 6, the pyrimidylaminobenzamderivatives chemical compound of its Chinese style (I) is 4-methyl-3-[[4-(3-pyridine radicals)-2-pyrimidine radicals] amino]-N-[5-(4-methyl isophthalic acid H-imidazoles-1-yl)-3-(trifluoromethyl) phenyl] Benzoylamide.
8. claim 2,3,6 or 7 method, it comprises the pyrimidylaminobenzamderivatives combination of compounds of using RAF inhibitor and formula (I), and RAF inhibitor wherein is selected from (the 4-tert-butyl group-phenyl)-(4-pyridine radicals-4-ylmethyl-isoquinolyl-1)-amine; [4,7 ']-two isoquinolyl-1s-4-(tert-butyl group-phenyl)-amine; (the 4-tert-butyl group-phenyl)-(4-quinazoline-6-base-isoquinolyl-1)-amine; [4,7 '] two isoquinolyl-1s-(the 2-tert-butyl group-pyrimidine-5-yl)-amine and its combination.
9. according to the combination product of claim 1 or claim 4,6 or 7 purposes, RAF inhibitor wherein is selected from (the 4-tert-butyl group-phenyl)-(4-pyridin-4-yl methyl-isoquinolyl-1)-amine; [4,7 '] two isoquinolyl-1s-4-(tert-butyl group-phenyl)-amine; (the 4-tert-butyl group-phenyl)-(4-quinazoline-6-base-isoquinolyl-1)-amine; [4,7 '] two isoquinolyl-1s-(the 2-tert-butyl group-pyrimidine-5-yl)-amine and its combination.
10. comprise commercial packing according to combination product any in the claim 1,4 or 5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65634005P | 2005-02-25 | 2005-02-25 | |
| US60/656,340 | 2005-02-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101160131A true CN101160131A (en) | 2008-04-09 |
Family
ID=36168564
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800126516A Pending CN101160131A (en) | 2005-02-25 | 2006-02-24 | Pharmaceutical combination of bcr-abl and raf inhibitors |
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| Country | Link |
|---|---|
| US (1) | US20080207658A1 (en) |
| EP (1) | EP1863491A1 (en) |
| KR (1) | KR20070106036A (en) |
| CN (1) | CN101160131A (en) |
| AU (1) | AU2006218020A1 (en) |
| CA (1) | CA2601687A1 (en) |
| MX (1) | MX2007011866A (en) |
| RU (1) | RU2007135284A (en) |
| WO (1) | WO2006089781A1 (en) |
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| EP1923053A1 (en) * | 2006-09-27 | 2008-05-21 | Novartis AG | Pharmaceutical compositions comprising nilotinib or its salt |
| CA2689989A1 (en) | 2007-06-04 | 2008-12-11 | Avila Therapeutics, Inc. | Heterocyclic compounds and uses thereof |
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| DE69942097D1 (en) * | 1998-08-11 | 2010-04-15 | Novartis Ag | ISOCHINOLINE DERIVATIVES WITH ANGIOGENESIS-HEMMENDER EFFECT |
| MXPA03009648A (en) * | 2001-04-20 | 2005-10-05 | Bayer Ag | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas. |
| GB0215676D0 (en) * | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
| BRPI0408257A (en) * | 2003-03-11 | 2006-03-07 | Novartis Ag | use of isoquinoline derivatives to treat cancer and kinase related diseases map |
| CA2522333A1 (en) * | 2003-04-14 | 2004-10-21 | Novartis Ag | Methods for treating proliferative diseases and for monitoring the effectiveness of treatment of proliferative diseases |
| EP1635835B1 (en) * | 2003-06-13 | 2010-01-06 | Novartis AG | 2-aminopyrimidine derivatives as raf kinase inhibitors |
| EP1667721A2 (en) * | 2003-09-23 | 2006-06-14 | Novartis AG | Combinations of a vegf receptor inhibitor with other therapeutic agents |
| PE20050952A1 (en) * | 2003-09-24 | 2005-12-19 | Novartis Ag | DERIVATIVES OF ISOQUINOLINE AS INHIBITORS OF B-RAF |
-
2006
- 2006-02-24 AU AU2006218020A patent/AU2006218020A1/en not_active Abandoned
- 2006-02-24 WO PCT/EP2006/001740 patent/WO2006089781A1/en active Application Filing
- 2006-02-24 US US11/909,013 patent/US20080207658A1/en not_active Abandoned
- 2006-02-24 RU RU2007135284/15A patent/RU2007135284A/en unknown
- 2006-02-24 EP EP06707271A patent/EP1863491A1/en not_active Withdrawn
- 2006-02-24 KR KR1020077021857A patent/KR20070106036A/en not_active Application Discontinuation
- 2006-02-24 CA CA002601687A patent/CA2601687A1/en not_active Abandoned
- 2006-02-24 CN CNA2006800126516A patent/CN101160131A/en active Pending
- 2006-02-24 MX MX2007011866A patent/MX2007011866A/en unknown
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| EP1863491A1 (en) | 2007-12-12 |
| RU2007135284A (en) | 2009-03-27 |
| KR20070106036A (en) | 2007-10-31 |
| MX2007011866A (en) | 2007-10-10 |
| US20080207658A1 (en) | 2008-08-28 |
| AU2006218020A1 (en) | 2006-08-31 |
| CA2601687A1 (en) | 2006-08-31 |
| WO2006089781A1 (en) | 2006-08-31 |
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